Methods Of Providing Weight Loss Therapy In Patients With Major Depression

ABSTRACT

Disclosed are methods of providing weight loss therapy, particularly for patients suffering from major depression.

RELATED APPLICATION INFORMATION

The present application is a continuation of U.S. application Ser. No.12/987,909, filed Jan. 10, 2011, which claims the benefit of priority toU.S. Provisional Patent Application Ser. No. 61/293,844, filed Jan. 11,2010, each of which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to methods of providing weight losstherapy, particularly for patients suffering from major depression.

Description of the Related Art

Obesity has been defined in terms of body mass index (BMI). BMI iscalculated as weight (kg)/[height (m)]². According to the guidelines ofthe U.S. Centers for Disease Control and Prevention (CDC) and the WorldHealth Organization (WHO), for adults over 20 years old, BMI falls intoone of the following categories: below 18.5 is considered underweight,18.5-24.9 is considered normal, 25.0-29.9 is considered overweight, and30.0 and above is considered obese (World Health Organization. Physicalstatus: The use and interpretation of anthropometry. Geneva,Switzerland: World Health Organization 1995. WHO Technical ReportSeries).

The diagnosis of mental disorders is typically based on the criteriaprovided in the Diagnostic and Statistical Manual of Mental Disorders,fourth edition (DSM-IV) (American Psychiatric Association; Diagnosticand Statistical Manual of Mental Disorders, fourth edition (DSM-IV),Washington, D.C., American Psychiatric Press, 1994). Three majorcategories of depression described in the DSM-IV are major depressivedisorder (i.e., unipolar major depression), dysthymic disorder (i.e.,dysthymia), and bipolar disorder (i.e., manic-depressive illness). Thereare also several subtypes of these main categories of depression. Forexample, atypical depression is a subtype of all three main types ofdepression that is characterized by the capacity to be cheered up whenpresented with positive events (see id.).

According to the DSM-IV, the essential feature of major depressivedisorder is a period of at least two weeks during which an individualexperiences a depressed mood or the loss of interest or pleasure innearly all activities (see id.). A diagnosis of major depressivedisorder also requires at least four additional symptoms that mayinclude changes in appetite or weight; insomnia; psychomotor agitationor retardation; decreased energy level; feelings of worthlessness orguilt; difficulty thinking, concentrating, or making decisions; andrecurrent thoughts of death, suicidal ideation, or attempts to commitsuicide (see id.).

In contrast, dysthymic disorder is a milder form of depression withsymptoms similar to, but less severe than, those of major depressivedisorder. Bipolar disorder is characterized by extreme swings in moodbetween mania and depression, with mania being accompanied by euphoria,grandiosity, increased energy, decreased need for sleep, rapid speech,and risk taking (see id.).

Depression has been linked to obesity, with recent studies identifying aspecific link between major depression (i.e., major depressive disorder)and overweight or obesity. Depression has also been linked to emotionaleating, which in turn is linked to high BMI. Further, depressed patientsare known to exhibit weight gain as a side effect of certain depressiontherapies.

U.S. Pat. Nos. 7,375,111 and 7,462,626 disclose the combination ofnaltrexone and bupropion for weight loss therapy. Further, U.S. Pat. No.5,817,665 discloses examples in which the combination of naltrexone andan antidepressant is used to treat depression in individuals who arealso obese or crave sweets. However, a need exists for an effectivemethod for the treatment of overweight or obesity in the difficult totreat population of overweight or obese patients suffering from majordepression. A need also exists for an effective method to concurrentlytreat major depression and overweight or obesity.

SUMMARY OF THE INVENTION

Disclosed herein are methods of providing weight loss therapy,particularly for patients suffering from major depression. In someembodiments, the methods unexpectedly provide the same amount of weightloss in overweight or obese patients who are suffering from majordepression as in overweight or obese patients who are not suffering frommajor depression. In some embodiments, the dosages of naltrexone andbupropion unexpectedly treat both overweight or obesity and majordepression.

In some embodiments, a method for providing weight loss therapy to apatient is provided, comprising: identifying a patient suffering frommajor depressive disorder, where the patient is also overweight orobese; and reducing weight of the patient by administering to thepatient naltrexone or a pharmaceutically acceptable salt thereof andbupropion or a pharmaceutically acceptable salt thereof, where thenaltrexone or pharmaceutically acceptable salt thereof is in an amounteffective to enhance the weight loss activity of the bupropion orpharmaceutically acceptable salt thereof. In certain embodiments, themethod further comprises reducing symptoms of depression in the patient.In certain embodiments, the patient has been diagnosed as suffering frommajor depressive disorder using the Montgomery-Asberg Depression RatingScale. In certain embodiments, the patient has been diagnosed assuffering from major depressive disorder using the Inventory ofDepressive Symptomatology. In certain embodiments, the patient is notsuffering from bipolar disorder. In certain embodiments, the patient hasa body mass index of 25 kg/m² or above. In certain embodiments, thepatient has a body mass index of 30 kg/m² or above. In certainembodiments, the patient is overweight. In certain embodiments, thepatient is obese. In certain embodiments, the patient is female. Incertain embodiments, the weight-loss inducing combination isadministered at least once per day. In certain embodiments, theweight-loss inducing combination is administered more than once per day.In certain embodiments, the weight-loss inducing combination isadministered for a period of at least 12 weeks. In certain embodiments,the weight-loss inducing combination is administered for a period of atleast 24 weeks. In certain embodiments, the naltrexone orpharmaceutically acceptable salt thereof is administered prior to orsubsequent to the bupropion or pharmaceutically acceptable salt thereof.In certain embodiments, the naltrexone or pharmaceutically acceptablesalt thereof and the bupropion or pharmaceutically acceptable saltthereof are in a single oral dosage form. In certain embodiments, thesingle oral dosage form further comprises a pharmaceutically acceptableexcipient, diluent, or carrier. In certain embodiments, the amount ofnaltrexone or pharmaceutically acceptable salt thereof is about 5 mg toabout 50 mg per day. In certain embodiments, the amount of bupropion orpharmaceutically acceptable salt thereof is about 30 mg to about 500 mgper day. In certain embodiments, the amount of the naltrexone orpharmaceutically acceptable salt thereof is about 5 mg to about 50 mgper day; and the amount of the bupropion or pharmaceutically acceptablesalt thereof is about 30 mg to about 500 mg per day. In certainembodiments, the amount of the naltrexone or pharmaceutically acceptablesalt thereof is about 4 mg to about 50 mg per day; and the amount of thebupropion or pharmaceutically acceptable salt thereof is about 30 mg toabout 500 mg per day. In certain embodiments, the amount of naltrexoneor pharmaceutically acceptable salt thereof is about 16 mg or about 32mg per day; and the amount of bupropion or pharmaceutically acceptablesalt thereof is about 360 mg per day. In certain embodiments, theinitial daily dose administered to the patient is about 4 mg or about 8mg of the naltrexone or pharmaceutically acceptable salt thereof andabout 90 mg of the bupropion or pharmaceutically acceptable saltthereof; and the daily dose administered to the patient for maintenanceis about 16 mg or about 32 mg of the naltrexone or pharmaceuticallyacceptable salt thereof and about 360 mg of the bupropion orpharmaceutically acceptable salt thereof. In certain embodiments, thedaily dose of the naltrexone or pharmaceutically acceptable salt thereofis a dosing schedule selected from the group consisting of 4 mg in weekone to 8 mg in week two, 12 mg in week three, and 16 mg in week four andthereafter and 8 mg in week one to 16 mg in week two, 24 mg in weekthree, and 32 mg in week four and thereafter; and the daily dose of thebupropion or pharmaceutically acceptable salt thereof is escalated from90 mg in week one to 180 mg in week two, 270 mg in week three, and 360mg in week four and thereafter. In certain embodiments, the amount ofnaltrexone or pharmaceutically acceptable salt thereof is about 32 mgper day; and the amount of bupropion or pharmaceutically acceptable saltthereof is about 360 mg per day. In certain embodiments, the methodfurther comprises adjusting the dosage of the naltrexone orpharmaceutically acceptable salt thereof, the bupropion orpharmaceutically acceptable salt thereof, or both as needed to treat thepatient's major depressive disorder. In certain embodiments, the methodfurther comprises adjusting the dosage of the naltrexone orpharmaceutically acceptable salt thereof, the bupropion orpharmaceutically acceptable salt thereof, or both as needed to treat thepatient's overweight or obesity. In certain embodiments, at least one ofthe naltrexone or pharmaceutically acceptable salt thereof and bupropionor pharmaceutically acceptable salt thereof is in a sustained releaseformulation. In certain embodiments, each of the naltrexone orpharmaceutically acceptable salt thereof and bupropion orpharmaceutically acceptable salt thereof is in a sustained releaseformulation. In certain embodiments, the method further comprisesadministering the naltrexone or pharmaceutically acceptable salt thereofand bupropion or pharmaceutically acceptable salt thereof with food.

In some embodiments, a method for providing weight loss therapy to apatient is provided, comprising: identifying a patient suffering frommajor depressive disorder, wherein the patient is also overweight orobese; and reducing weight of the patient by administering to thepatient naltrexone or a pharmaceutically acceptable salt thereof andbupropion or a pharmaceutically acceptable salt thereof, where theamount of the naltrexone or pharmaceutically acceptable salt thereof isabout 32 mg per day; where the amount of the bupropion orpharmaceutically acceptable salt thereof is about 360 mg per day; andwhere each of the naltrexone or pharmaceutically acceptable salt thereofand bupropion or pharmaceutically acceptable salt thereof is in asustained release formulation.

In some embodiments, a method for selecting a weight loss therapy fromamong available weight loss therapies is provided, comprising:evaluating a patient to asses whether the patient is simultaneously inneed of weight loss therapy and depression therapy; and if so, providingto the patient an effective weight-loss-inducing and antidepressantcombination of bupropion or a pharmaceutically acceptable salt thereofand naltrexone or a pharmaceutically acceptable salt thereof as activeingredients. In certain embodiments, the method further comprisesproviding printed information to the patient indicating that thecombination promotes weight loss and reduces symptoms of depression. Incertain embodiments, the patient has been diagnosed as suffering frommajor depressive disorder using the Montgomery-Åsberg Depression RatingScale. In certain embodiments, the patient has been diagnosed assuffering from major depressive disorder using the Inventory ofDepressive Symptomatology. In certain embodiments, the patient is notsuffering from bipolar disorder. In certain embodiments, the patient hasa body mass index of 25 kg/m² or above. In certain embodiments, thepatient has a body mass index of 30 kg/m² or above. In certainembodiments, the patient is overweight. In certain embodiments, thepatient is obese. In certain embodiments, the patient is female. Incertain embodiments, the weight-loss-inducing and antidepressantcombination is administered at least once per day. In certainembodiments, the weight-loss-inducing and antidepressant combination isadministered more than once per day. In certain embodiments, theweight-loss-inducing and antidepressant combination is administered fora period of at least 12 weeks. In certain embodiments, theweight-loss-inducing and antidepressant combination is administered fora period of at least 24 weeks. In certain embodiments, the naltrexone orpharmaceutically acceptable salt thereof is administered prior to orsubsequent to the bupropion or pharmaceutically acceptable salt thereof.In certain embodiments, the naltrexone or pharmaceutically acceptablesalt thereof and the bupropion or pharmaceutically acceptable saltthereof are in a single oral dosage form. In certain embodiments, thesingle oral dosage form further comprises a pharmaceutically acceptableexcipient, diluent, or carrier. In certain embodiments, the amount ofnaltrexone or pharmaceutically acceptable salt thereof is about 5 mg toabout 50 mg per day. In certain embodiments, the amount of bupropion orpharmaceutically acceptable salt thereof is about 30 mg to about 500 mgper day. In certain embodiments, the amount of the naltrexone orpharmaceutically acceptable salt thereof is about 5 mg to about 50 mgper day; and the amount of the bupropion or pharmaceutically acceptablesalt thereof is about 30 mg to about 500 mg per day. In certainembodiments, the amount of the naltrexone or pharmaceutically acceptablesalt thereof is about 4 mg to about 50 mg per day; and the amount of thebupropion or pharmaceutically acceptable salt thereof is about 30 mg toabout 500 mg per day. In certain embodiments, the amount of naltrexoneor pharmaceutically acceptable salt thereof is about 16 mg or about 32mg per day; and the amount of bupropion or pharmaceutically acceptablesalt thereof is about 360 mg per day. In certain embodiments, theinitial daily dose administered to the patient is about 4 mg or about 8mg of the naltrexone or pharmaceutically acceptable salt thereof andabout 90 mg of the bupropion or pharmaceutically acceptable saltthereof; and the daily dose administered to the patient for maintenanceis about 16 mg or about 32 mg of the naltrexone or pharmaceuticallyacceptable salt thereof and about 360 mg of the bupropion orpharmaceutically acceptable salt thereof. In certain embodiments, thedaily dose of the naltrexone or pharmaceutically acceptable salt thereofis a dosing schedule selected from the group consisting of 4 mg in weekone to 8 mg in week two, 12 mg in week three, and 16 mg in week four andthereafter and 8 mg in week one to 16 mg in week two, 24 mg in weekthree, and 32 mg in week four and thereafter; and the daily dose of thebupropion or pharmaceutically acceptable salt thereof is escalated from90 mg in week one to 180 mg in week two, 270 mg in week three, and 360mg in week four and thereafter. In certain embodiments, the amount ofnaltrexone or pharmaceutically acceptable salt thereof is about 32 mgper day; and the amount of bupropion or pharmaceutically acceptable saltthereof is about 360 mg per day. In certain embodiments, the methodfurther comprises adjusting the dosage of the naltrexone orpharmaceutically acceptable salt thereof, the bupropion orpharmaceutically acceptable salt thereof, or both as needed to treat thepatient's major depressive disorder. In certain embodiments, the methodfurther comprises adjusting the dosage of the naltrexone orpharmaceutically acceptable salt thereof, the bupropion orpharmaceutically acceptable salt thereof, or both as needed to treat thepatient's overweight or obesity. In certain embodiments, at least one ofthe naltrexone or pharmaceutically acceptable salt thereof and bupropionor pharmaceutically acceptable salt thereof is in a sustained releaseformulation. In certain embodiments, each of the naltrexone orpharmaceutically acceptable salt thereof and bupropion orpharmaceutically acceptable salt thereof is in a sustained releaseformulation. In certain embodiments, the method further comprisesadministering the naltrexone or pharmaceutically acceptable salt thereofand bupropion or pharmaceutically acceptable salt thereof with food.

In some embodiments, a method for providing weight loss therapy to apatient is provided, comprising: providing to the patient a drug productcomprising an effective weight-loss inducing combination of bupropion ora pharmaceutically acceptable salt thereof and naltrexone or apharmaceutically acceptable salt thereof as active ingredients; andproviding to the patient printed information indicating that indepressed patients, the drug product results in a promotion of weightloss and a reduction of symptoms of depression. In certain embodiments,the patient has been diagnosed as suffering from major depressivedisorder using the Montgomery-Asberg Depression Rating Scale. In certainembodiments, the patient has been diagnosed as suffering from majordepressive disorder using the Inventory of Depressive Symptomatology. Incertain embodiments, the patient is not suffering from bipolar disorder.In certain embodiments, the patient has a body mass index of 25 kg/m² orabove. In certain embodiments, the patient has a body mass index of 30kg/m² or above. In certain embodiments, the patient is overweight. Incertain embodiments, the patient is obese. In certain embodiments, thepatient is female. In certain embodiments, the drug product isadministered at least once per day. In certain embodiments, the drugproduct is administered more than once per day. In certain embodiments,the drug product is administered for a period of at least 12 weeks. Incertain embodiments, the drug product is administered for a period of atleast 24 weeks. In certain embodiments, the naltrexone orpharmaceutically acceptable salt thereof is administered prior to orsubsequent to the bupropion or pharmaceutically acceptable salt thereof.In certain embodiments, the naltrexone or pharmaceutically acceptablesalt thereof and the bupropion or pharmaceutically acceptable saltthereof are in a single oral dosage form. In certain embodiments, thesingle oral dosage form further comprises a pharmaceutically acceptableexcipient, diluent, or carrier. In certain embodiments, the amount ofnaltrexone or pharmaceutically acceptable salt thereof is about 5 mg toabout 50 mg per day. In certain embodiments, the amount of bupropion orpharmaceutically acceptable salt thereof is about 30 mg to about 500 mgper day. In certain embodiments, the amount of the naltrexone orpharmaceutically acceptable salt thereof is about 5 mg to about 50 mgper day; and the amount of the bupropion or pharmaceutically acceptablesalt thereof is about 30 mg to about 500 mg per day. In certainembodiments, the amount of the naltrexone or pharmaceutically acceptablesalt thereof is about 4 mg to about 50 mg per day; and the amount of thebupropion or pharmaceutically acceptable salt thereof is about 30 mg toabout 500 mg per day. In certain embodiments, the amount of naltrexoneor pharmaceutically acceptable salt thereof is about 16 mg or about 32mg per day; and the amount of bupropion or pharmaceutically acceptablesalt thereof is about 360 mg per day. In certain embodiments, theinitial daily dose administered to the patient is about 4 mg or about 8mg of the naltrexone or pharmaceutically acceptable salt thereof andabout 90 mg of the bupropion or pharmaceutically acceptable saltthereof; and the daily dose administered to the patient for maintenanceis about 16 mg or about 32 mg of the naltrexone or pharmaceuticallyacceptable salt thereof and about 360 mg of the bupropion orpharmaceutically acceptable salt thereof. In certain embodiments, thedaily dose of the naltrexone or pharmaceutically acceptable salt thereofis a dosing schedule selected from the group consisting of 4 mg in weekone to 8 mg in week two, 12 mg in week three, and 16 mg in week four andthereafter and 8 mg in week one to 16 mg in week two, 24 mg in weekthree, and 32 mg in week four and thereafter; and the daily dose of thebupropion or pharmaceutically acceptable salt thereof is escalated from90 mg in week one to 180 mg in week two, 270 mg in week three, and 360mg in week four and thereafter. In certain embodiments, the amount ofnaltrexone or pharmaceutically acceptable salt thereof is about 32 mgper day; and the amount of bupropion or pharmaceutically acceptable saltthereof is about 360 mg per day. In certain embodiments, the methodfurther comprises adjusting the dosage of the naltrexone orpharmaceutically acceptable salt thereof, the bupropion orpharmaceutically acceptable salt thereof, or both as needed to treat thepatient's major depressive disorder. In certain embodiments, the methodfurther comprises adjusting the dosage of the naltrexone orpharmaceutically acceptable salt thereof, the bupropion orpharmaceutically acceptable salt thereof, or both as needed to treat thepatient's overweight or obesity. In certain embodiments, at least one ofthe naltrexone or pharmaceutically acceptable salt thereof and bupropionor pharmaceutically acceptable salt thereof is in a sustained releaseformulation. In certain embodiments, each of the naltrexone orpharmaceutically acceptable salt thereof and bupropion orpharmaceutically acceptable salt thereof is in a sustained releaseformulation. In certain embodiments, the method further comprisesadministering the naltrexone or pharmaceutically acceptable salt thereofand bupropion or pharmaceutically acceptable salt thereof with food.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

In some embodiments, the method is effective to reduce the symptoms ofmajor depression. In some embodiments, the reduction in symptoms ofmajor depression is measured by a percent change from baseline symptomsbefore treatment. In some embodiments, the reduction in symptoms ofmajor depression is measured by a change in a Montgomery-AsbergDepression Rating Scale score. In some embodiments, the reduction insymptoms of major depression is measured by a change in an Inventory ofDepressive Symptomatology-Self Report (IDS-SR) score. In someembodiments, the reduction in symptoms of major depression is measuredby a change as assessed by the Clinical Global Impressions-Improvement(CGI-I) scale. In some of these embodiments, the reduction in symptomsof major depression is measured by a change in response and/or remissionrates of depressive symptoms. In a preferred embodiment, the reductionin symptoms of major depression is at least about 40%. In someembodiments, the reduction in symptoms of major depression is, is about,is at least, is at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, ora range defined by any two of the preceding values. In some embodiments,a reduction in symptoms of major depression is seen at about 4, 8, 12,16, 20, 24, 36, 48, or 52 weeks, or a range defined by any two of thepreceding values.

In some embodiments, the method is effective to promote weight loss ormitigate weight gain in an overweight or obese individual. In someembodiments, the individual has gained weight as a result of depressionand/or as a result of being administered another drug product for thetreatment of depression. However, in some embodiments, the cause of theindividual's overweight or obesity is unknown. In some embodiments, amethod of promoting weight loss or mitigating weight gain and reducingsymptoms of major depression is provided. In some embodiments, a methodof reducing symptoms of major depression is provided regardless ofweight loss or mitigation of weight gain. In some embodiments, a methodof promoting weight loss or mitigating weight gain is providedregardless of a reduction in symptoms of major depression.

In some embodiments, the individual has a body mass index (BMI) of atleast 25 kg/m². In some embodiments, the individual has a BMI of atleast 30 kg/m². In some embodiments, the individual has a BMI of atleast 40 kg/m². In some embodiments, the individual has a BMI of lessthan 25 kg/m², or develops a BMI less than 25 kg/m² during the course ofadministration of naltrexone and bupropion. In these embodiments, it maybe beneficial for health or cosmetic purposes to mitigate subsequentweight gain or to promote weight loss, thereby reducing the BMI evenfurther. In some embodiments, the individual has been diagnosed by aphysician as being overweight or obese. In some embodiments, theindividual is identified, including self-identified, as overweight orobese, or is identified as having been diagnosed as overweight or obese.

In some embodiments, the promotion of weight loss is measured by apercent change from a baseline body weight. In some of theseembodiments, the amount of weight loss is, is about, is at least, is atleast about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%,12%, 15%, or more of initial body weight, or a range defined by any twoof the preceding values. In some embodiments, the promotion of weightloss is measured as a reduction in weight gain relative to the amount ofweight gain experienced when neither or only one of naltrexone andbupropion is administered, and the amount of reduction in weight gainis, is about, is at least, is at least about, 2%, 5%, 10%, 15%, 20%,25%, 30% 40%, 50%, 60%, 70%, 80%, 90%, 100%, 105%, 110%, 115%, 120%, ormore, or a range defined by any two of the preceding values.

In some embodiments, the mitigation of weight gain is measured by apercent change from a baseline body weight. In some of theseembodiments, the amount of weight gain is, is about, is not more than,is not more than about 0%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, 6%, 7%,8%, 9%, 10% or more of initial body weight, or a range defined by anytwo of the preceding values.

In some embodiments, the dosage is adjusted so that the patient losesweight at a rate of about 3% of baseline body weight every six months.However, the rate of weight loss for a patient may be adjusted by thetreating physician based on the patient's particular needs. In someembodiments, the dosage is adjusted so that the patient exhibits a 50%reduction in symptoms of depression every six months. However, the rateof reduction in symptoms of depression for a patient may also beadjusted by the treating physician based on the patient's particularneeds.

In some embodiments, the mitigation of weight gain or promotion ofweight loss occurs by increasing satiety in the individual. In someembodiments, the mitigation of weight gain or promotion of weight lossoccurs by suppressing the appetite of the individual. In someembodiments, the individual receives depression or weight losscounseling, or both. In some embodiments, the method further comprisesinstituting a regimen of diet and/or increased activity. In someembodiments, the individual is co-administered another drug product forthe treatment of depression. For example, in some embodiments, theindividual is co-administered venlafaxine, duloxetine, or aripiprazole.

In some embodiments, treatment of an obese person undergoing or about tobegin a period of treatment for depression results in greater mitigationof weight gain or promotion of weight loss than that observed whentreating an overweight or normal weight person undergoing or about tobegin treatment for depression. In some embodiments, treatment of anobese person undergoing or about to begin a period of treatment fordepression results in greater mitigation of weight gain or promotion ofweight loss than that observed when treating an obese or overweightperson not suffering from depression with bupropion and naltrexone.

In some embodiments, treatment of an overweight person undergoing orabout to begin a period of treatment for depression results in greatermitigation of weight gain or promotion of weight loss than that observedwhen treating an obese or normal weight person undergoing or about tobegin treatment for depression. In some embodiments, treatment of anoverweight person undergoing or about to begin a treatment fordepression results in greater mitigation of weight gain or promotion ofweight loss than that observed when treating an obese or overweightperson not suffering from depression with bupropion and naltrexone.

In some embodiments, the treatment works as well or better for treatingobesity or overweight in an obese or overweight person suffering frommajor depression as it does for an obese, overweight, or normal weightperson not suffering from major depression. For example, in someembodiments, the treatment results in the same weight loss in an obeseor overweight person suffering from depression as it would in an obeseor overweight person not suffering from depression. In some embodiments,the treatment results in greater weight loss in an obese or overweightperson suffering from depression as it would in an obese or overweightperson not suffering from depression.

In some embodiments, the treatment works as well or better for treatingdepression in an obese or overweight person suffering from majordepression as it does for a normal weight person suffering from majordepression. For example, in some embodiments, the treatment results inthe same reduction in symptoms of depression for an obese or overweightperson as it would in a normal weight person. In some embodiments, thetreatment results in a greater reduction in the symptoms of depressionin an obese or overweight person suffering from depression as it wouldin a normal weight person suffering from depression.

In some embodiments, naltrexone and bupropion are each administered onceper day. In some embodiments, naltrexone and bupropion are each dividedinto equal doses and administered more than once per day. In someembodiments, naltrexone and bupropion are each divided into unequaldoses and administered more than once per day. In some embodiments,naltrexone and bupropion are divided into a different number of dosesand are administered a different number of times per day. In one suchembodiment, the dose of one of naltrexone or bupropion is divided, whilethe dose of the other is not.

In some embodiments, one or both of naltrexone and bupropion isadministered one, two, three, four, or more times per day. In someembodiments, one or both of naltrexone and bupropion are administered ina controlled release formulation. Either or both compounds can beadministered less than once per day, for example once every 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, or 14 days, or every 1 or 2 weeks, or arange defined by any two of the preceding values.

The exact formulation, route of administration, and dosage fornaltrexone and bupropion combinations described herein can be chosen bythe individual physician in view of the patient's condition. (See e.g.,Fingl et al. 1975, in “The Pharmacological Basis of Therapeutics,” Ch. 1p. 1). In some embodiments, the daily dose of naltrexone and bupropionis the same, and in some embodiments, the daily dose is different.

In some embodiments, the daily dose of naltrexone can range from about 4mg to about 50 mg, or about 4 mg to about 32 mg, or about 8 mg to about32 mg, or about 8 mg to about 16 mg. In some embodiments, the daily doseis about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 32 mg, orabout 48 mg of naltrexone, or a range defined by any two of thepreceding values. In some embodiments, the daily dose is administered ina single oral dosage form. The selection of a particular dosage may bebased on the weight of the patient. The selection of a particular dosagemay be based on the identity, dosage, and/or dosing schedule of anotherco-administered compound. However, in some embodiments, it may benecessary to use dosages outside these ranges.

In some embodiments, the daily dose of bupropion can range from about 30mg to about 500 mg, or about 30 mg to about 360 mg, or about 90 mg toabout 360 mg. In some embodiments, the daily dose is about 30 mg, about90 mg, about 180 mg, about 360 mg, or about 450 mg of bupropion, or arange defined by any two of the preceding values. In some embodiments,the daily dose is administered in a single oral dosage form. Theselection of a particular dosage may be based on the weight of thepatient. The selection of a particular dosage may be based on theidentity, dosage and/or dosing schedule of another co-administeredcompound. However, in some embodiments, it may be necessary to usedosages outside these ranges.

In some embodiments, at least one of naltrexone and bupropion isadministered with varying frequency during treatment. In some of theseembodiments, the varying frequency comprises a decreased frequency overtime. For example, one or both of naltrexone and bupropion can beinitially administered more than once per day, followed byadministration only once per day at a later point in treatment. In someembodiments, the daily dosage of at least one of naltrexone andbupropion is consistent despite the varying frequency of administration.For example, in some embodiments, two tablets of each of naltrexone andbupropion are initially administered twice per day, while four tabletsof each of naltrexone and bupropion are administered once per day at alater point in treatment. Alternatively, in some embodiments, one or twotablets of each of naltrexone and bupropion are administered at a laterpoint in treatment, where the one or two tablets have an equivalenttotal daily dosage as the two tablets each of naltrexone and bupropioninitially administered twice per day.

In some embodiments where one or both of naltrexone and bupropion areadministered less than once per day in a controlled release or sustainedrelease (SR) formulation, the dose is selected so that the patientreceives a daily dose that is about the same as a daily dose describedherein.

In some embodiments, at least one of naltrexone or bupropion isadministered in consistent daily dosages throughout the period oftreatment. In some embodiments, at least one of naltrexone or bupropionis administered in varying daily dosages during the period of treatment.In some of these embodiments, the daily dosages comprise increasingdaily dosages over time. In some of these embodiments, the daily dosagescomprise decreasing daily dosages over time.

In some embodiments, naltrexone and bupropion are administeredindividually. In some embodiments, naltrexone and bupropion areadministered in a single pharmaceutical composition comprisingnaltrexone and bupropion. In some embodiments, at least one ofnaltrexone or bupropion is in a sustained release or controlled releaseformulation. For example, sustained release forms of naltrexone aredescribed in U.S. Patent Publication No. 2007/0281021, which isincorporated herein by reference in its entirety and for all purposes,including without limitation for the purpose of describing sustainedrelease forms of naltrexone and bupropion, methods of making andformulating them into suitable dosage forms, and methods ofadministering them. In some embodiments, at least one of naltrexone orbupropion is administered with a physiologically acceptable carrier,diluent, or excipient, or a combination thereof. Non-limiting examplesof naltrexone/bupropion combinations, formulations thereof, and methodsof administering them are disclosed in U.S. Pat. Nos. 7,375,111 and7,462,626, both of which are incorporated herein by reference in theirentirety and for all purposes, including without limitation for thepurpose of describing combinations of naltrexone and bupropion, methodsof making and formulating them into suitable dosage forms, and methodsof administering them. Reference herein to the use or administration ofnaltrexone/bupropion combinations will be understood to include allmodes of administration disclosed or referred to herein, includingwithout limitation separate administration, administration in a singledosage form, administration in the form of salts, prodrugs and/ormetabolites, and/or administration in sustained release forms.Techniques for formulation and administration of the compounds of theinstant application may be found in “Remington's PharmaceuticalSciences,” Mack Publishing Co., Easton, Pa., 18th edition, 1990, whichis incorporated herein by reference in its entirety.

In some embodiments, naltrexone is administered prior to the bupropion.In some embodiments, naltrexone is administered subsequent to thebupropion. In some embodiments, naltrexone and the bupropion areco-administered. As used herein, co-administration includesadministration in a single dosage form, or separate dosage forms thatare administered at, or nearly at, the same time.

In some embodiments, the administration of naltrexone and bupropion iscontinued for a period of, or of about, 4, 12, 16, 20, 24, 36, 48, or 52weeks, or a range defined by any two of the preceding values. In someembodiments, the administration of naltrexone and bupropion is continueduntil the reduction in symptoms of depression is stabilized for a periodof, or of about, 1, 2, 3, 4, 5, 6, or more weeks, or a range defined byany two of the preceding values. In some embodiments, the administrationof naltrexone and bupropion is continued until the mitigation of weightgain or promotion of weight loss is stabilized for a period of, or ofabout, 1, 2, 3, 4, 5, 6, or more weeks, or a range defined by any two ofthe preceding values. In some embodiments, administration of naltrexoneand bupropion is continued until the individual no longer needstreatment for major depressive disorder. In some embodiments,administration of naltrexone and bupropion is continued until theindividual no longer needs treatment for obesity or overweight.

The compositions described herein may, if desired, be presented in apack or dispenser device which may contain one or more unit dosage formscontaining one or both of the active ingredients. The pack may, forexample, comprise metal or plastic foil, such as a blister pack. Thepack or dispenser device may be accompanied by instructions foradministration. The pack or dispenser may also be accompanied with anotice associated with the container in form prescribed by agovernmental agency regulating the manufacture, use, or sale ofpharmaceuticals, which notice is reflective of approval by the agency ofthe form of the drug for human administration. Such notice, for example,may be the labeling approved by the U.S. Food and Drug Administrationfor prescription drugs, or the approved product insert. Compositionscomprising a compound of the invention formulated in a compatiblepharmaceutical carrier may also be prepared, placed in an appropriatecontainer, and labeled for treatment of an indicated condition.Non-limiting examples of packs and dispensers as well as oral dosageforms are disclosed in U.S. Patent Publication Nos. 2008-0110792 and2008-0113026, both of which are hereby incorporated herein by referencein their entirety and for all purposes, including without limitation forthe purpose of describing combinations of naltrexone and bupropion,methods of making and formulating them into suitable dosage forms,methods of packing and dispensing them, and methods of administeringthem.

In some embodiments, the single oral dosage form comprises a pluralityof layers. For example, in some embodiments, the single oral dosage formis a trilayer tablet with a first pharmaceutical layer, a secondpharmaceutical layer, and an intermediate layer disposed between thefirst and second pharmaceutical layers that is configured to rapidlydissolve in vivo. Non-limiting examples of multilayer tablets aredisclosed in U.S. Patent Application Nos. 2008-0110792 and 2008-0113026,both of which are hereby incorporated herein by reference in theirentirety and for all purposes.

Instructions and/or information may be present in a variety of forms,including printed information on a suitable medium or substrate (e.g., apiece or pieces of paper on which the information is printed), computerreadable medium (e.g., diskette, CD, etc., on which the information hasbeen recorded), or a website address that may be accessed via theinternet. Printed information may, for example, be provided on a labelassociated with a drug product, on the container for a drug product,packaged with a drug product, or separately given to the patient apartfrom a drug product, or provided in manner that the patient canindependently obtain the information (e.g., a website). Printedinformation may also be provided to a medical caregiver involved intreatment of the patient.

Throughout the present disclosure, when a particular compound ismentioned by name, for example, bupropion or naltrexone, it isunderstood that the scope of the present disclosure encompassespharmaceutically acceptable salts, esters, amides, metabolites, orprodrugs of the named compound. For example, in any of the embodimentsherein, an active metabolite of naltrexone, e.g., 6-β naltrexol, can beused in combination with, or instead of, naltrexone. In any of theembodiments herein, an active metabolite of bupropion, includingS,S-hydroxybupropion (i.e., radafaxine), can be used in combinationwith, or instead of, bupropion.

As used herein, “mitigate” or “mitigation” of weight gain includespreventing or decreasing the amount of weight gain associated withdepression or with the administration of another drug therapy fordepression. In some embodiments, mitigation is measured relative to theamount of weight gain typically experienced when only one or neither ofnaltrexone or bupropion is administered.

As used herein, “promotion” of weight loss includes causing weight lossrelative to a baseline weight for a least a portion of the period oftreatment. This includes an individual that initially gains some weight,but during the course of treatment loses weight relative to a baselineprior to beginning treatment, as well as individuals that regain aportion or all of the weight that is lost by the end of the treatmentperiod. In a preferred embodiment, at the end of the treatment period,the individual has lost weight relative to a baseline. In a preferredembodiment, mitigation of weight gain or promotion of weight loss in apatient administered naltrexone and bupropion is greater than whenneither or only one of naltrexone or bupropion is administered, and morepreferably an at least additive, or better than additive, orsynergistic, effect of administering the two compounds is achieved.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. Pharmaceutical salts can be obtained byroutine experimentation. Non-limiting examples of pharmaceuticallyacceptable salts include bupropion hydrochloride, radafaxinehydrochloride, naltrexone hydrochloride, and 613 naltrexolhydrochloride.

A “prodrug” refers to an agent that is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration to a greater extent than the parent.The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug, demonstrate increased palatability,or be easier to formulate. Non-limiting examples of suitable prodrugsinclude those described in U.S. Patent Publication No. 2007/0117827,which is incorporated herein by reference in its entirety and for allpurposes, including without limitation for the purposes of describingnaltrexone metabolites and prodrugs thereof, methods of making andformulating them into suitable dosage forms, and methods ofadministering them.

It will be understood by those of skill in the art that numerous andvarious modifications can be made without departing from the spirit ofthe present invention. Therefore, it should be clearly understood thatthe embodiments of the present invention disclosed herein areillustrative only and are not intended to limit the scope of the presentinvention. Any reference referred to herein is incorporated by referencefor the material discussed herein, and in its entirety.

EXAMPLES

The examples below are non-limiting and are merely representative ofvarious aspects of the invention.

Example 1: Naltrexone and Bupropion

A 24-week open label study of sustained release naltrexone (naltrexoneSR) plus sustained release bupropion (bupropion SR) for depression andminimization of weight gain in subjects with BMI ≥27 and ≤43 kg/m² wasperformed according to the dose escalation schedule provided in Table 1.All subjects met the DSM-IV criteria for major depression (withoutpsychotic features) and had an IDS-SR total score ≥26.

TABLE 1 Morning Dose Evening Dose Total Daily Dose Week 1 one tablet (8mg — 8 mg naltrexone naltrexone SR + 90 mg SR/90 mg bupropion SR/tablet)bupropion SR Week 2 one tablet (8 mg one tablet (8 mg 16 mg naltrexonenaltrexone SR + 90 mg naltrexone SR + 90 mg SR/180 mg bupropionSR/tablet) bupropion SR/tablet) bupropion SR Week 3 two tablets (8 mgone tablet (8 mg 24 mg naltrexone naltrexone SR + 90 mg naltrexone SR +90 mg SR/270 mg bupropion SR/tablet) bupropion SR/tablet) bupropion SRWeek 4- two tablets (8 mg two tablets (8 mg 32 mg naltrexone Onwardnaltrexone SR + 90 mg naltrexone SR + 90 mg SR/360 mg bupropionSR/tablet) bupropion SR/tablet) bupropion SR

The primary outcomes were percent and absolute change from baseline intotal body weight and subject-reported depression at weeks 12 and 24.Other efficacy measures were: change in waist circumference; serumleptin and ghrelin levels; creatinine levels; and safety andtolerability. Adverse events and vital signs (e.g., systolic anddiastolic blood pressure and pulse) were used to monitor safety andtolerability. Of the 25 subjects enrolled, all were female, 23 wereCaucasian, and the average age was 47. All 25 subjects provided at leastone post-baseline evaluation, and 14 and 12 of the subjects completed 12and 24 weeks of treatment, respectively.

MADRS total scores decreased from 23.65 to 10.52 and 8.35 at weeks 12and 24, respectively. IDS-SR total scores decreased from 43.20 to about23 and 16 at weeks 12 and 24, respectively. CGI-I response rates were90.0% and 95.0% at weeks 12 and 24, respectively, as measured by fullanalysis set, last observation carried forward (FAS LOCF). CGI-Iremission rates were 55.0% and 70.0% at weeks 12 and 24, respectively,as measured by FAS LOCF. Total body weight decreased by 4.42% and 5.86%at weeks 12 and 24, respectively, as measured by FAS LOCF, and 6.75% and9.96% at weeks 12 and 24, respectively, as measured by observed case(OC) analysis. The most common adverse events were nausea, constipation,headache, insomnia, dizziness, and hot flush. In overweight or obesesubjects, naltrexone plus bupropion reduced symptoms of depression whilepreventing weight gain.

Example 2: Naltrexone and Bupropion

Patients having a BMI of greater than 25 are identified. Each patient isinstructed to take two 8 mg tablets of naltrexone (SR) twice daily, inaddition to two 90 mg tablets of bupropion (SR) twice daily.

The patients are monitored for a period of months. It is recommendedthat the dosage be adjusted so that each patient loses weight at a rateof at least about 3% of initial weight and exhibits a 50% reduction insymptoms of depression every six months. However, the rate of weightloss and reduction in symptoms of depression for each patient may beadjusted by the treating physician based on the patient's particularneeds.

If the initial dosage is not effective, then the dosage of either orboth of naltrexone and bupropion can be increased. Alternatively, if theinitial dosage results in a more rapid weight loss or reduction insymptoms of depression than the above rates, the dosage of either orboth of naltrexone and bupropion can be reduced.

Example 3: Naltrexone and Bupropion

In a multicenter, randomized, blinded, placebo-controlled clinicaltrial, the following drug combinations are tested:

Group 1—naltrexone (SR) 16 mg po BID + bupropion (SR) 180 mg po BIDGroup 2—N-placebo po BID + bupropion (SR) 180 mg po BID Group3—P-placebo po BID + naltrexone (SR) 16 mg po BID Group 4—N-placebo poBID + P-placebo po BID.

In any of the above groups, the dosage of naltrexone may be administeredin doses in the range between 5 mg and 50 mg, for example, 5 mg, 10 mg,15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, and 50 mg. In any ofthe above groups, the dosage of bupropion may be administered in dosesin the range between 30 mg and 500 mg, for example, 30 mg, 40 mg, 50 mg,60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, and 500 mg.

The primary endpoints are percent and absolute change from baseline intotal body weight and subject-reported depression at weeks 12 and 24.Secondary endpoints include percent and absolute change from baseline intotal body weight at weeks 36 and 48, change in waist circumference;serum leptin and ghrelin levels; creatinine levels; and safety andtolerability. Adverse events, laboratory parameters, and vital signs areused to monitor safety and tolerability.

What is claimed is:
 1. A method for providing weight loss therapy to apatient, comprising: identifying a patient suffering from majordepressive disorder, wherein the patient is also overweight or obese;and reducing weight of the patient by administering to the patientnaltrexone or a pharmaceutically acceptable salt thereof and bupropionor a pharmaceutically acceptable salt thereof, wherein the naltrexone orpharmaceutically acceptable salt thereof is in an amount effective toenhance the weight loss activity of the bupropion or pharmaceuticallyacceptable salt thereof.
 2. The method of claim 1, further comprisingreducing symptoms of depression in the patient.
 3. The method of claim1, wherein the patient is overweight.
 4. The method of claim 1, whereinthe patient is obese.
 5. The method of claim 1, wherein the naltrexoneor a pharmaceutically acceptable salt thereof and bupropion or apharmaceutically acceptable salt thereof is administered once per day.6. The method of claim 1, wherein the naltrexone or a pharmaceuticallyacceptable salt thereof and bupropion or a pharmaceutically acceptablesalt thereof is administered more than once per day.
 7. The method ofclaim 1, wherein the naltrexone or pharmaceutically acceptable saltthereof is administered prior to or subsequent to the bupropion orpharmaceutically acceptable salt thereof.
 8. The method of claim 1,wherein the naltrexone or pharmaceutically acceptable salt thereof andthe bupropion or pharmaceutically acceptable salt thereof are in asingle oral dosage form.
 9. The method of claim 8, wherein the singleoral dosage form further comprises a pharmaceutically acceptableexcipient, diluent, or carrier.
 10. The method of claim 1, wherein theamount of the naltrexone or pharmaceutically acceptable salt thereof isabout 4 mg to about 50 mg per day; and wherein the amount of thebupropion or pharmaceutically acceptable salt thereof is about 30 mg toabout 500 mg per day.
 11. The method of claim 1, wherein the amount ofnaltrexone or pharmaceutically acceptable salt thereof is about 16 mg orabout 32 mg per day; and wherein the amount of bupropion orpharmaceutically acceptable salt thereof is about 360 mg per day. 12.The method of claim 1, wherein the initial daily dose administered tothe patient is about 4 mg or about 8 mg of the naltrexone orpharmaceutically acceptable salt thereof and about 90 mg of thebupropion or pharmaceutically acceptable salt thereof; and wherein thedaily dose administered to the patient for maintenance is about 16 mg orabout 32 mg of the naltrexone or pharmaceutically acceptable saltthereof and about 360 mg of the bupropion or pharmaceutically acceptablesalt thereof.
 13. The method of claim 1, wherein the daily dose of thenaltrexone or pharmaceutically acceptable salt thereof is a dosingschedule selected from the group consisting of 4 mg in week one to 8 mgin week two, 12 mg in week three, and 16 mg in week four and thereafterand 8 mg in week one to 16 mg in week two, 24 mg in week three, and 32mg in week four and thereafter; and wherein the daily dose of thebupropion or pharmaceutically acceptable salt thereof is escalated from90 mg in week one to 180 mg in week two, 270 mg in week three, and 360mg in week four and thereafter.
 14. The method of claim 13, wherein atleast one of the naltrexone or pharmaceutically acceptable salt thereofand bupropion or pharmaceutically acceptable salt thereof is in asustained release formulation.
 15. The method of claim 14, wherein thenaltrexone or pharmaceutically acceptable salt thereof and the bupropionor pharmaceutically acceptable salt thereof are in a single oral dosageform.
 16. The method of claim 13, wherein each of the naltrexone orpharmaceutically acceptable salt thereof and bupropion orpharmaceutically acceptable salt thereof is in a sustained releaseformulation.
 17. The method of claim 16, wherein the naltrexone orpharmaceutically acceptable salt thereof and the bupropion orpharmaceutically acceptable salt thereof are in a single oral dosageform.
 18. The method of claim 1, wherein at least one of the naltrexoneor pharmaceutically acceptable salt thereof and bupropion orpharmaceutically acceptable salt thereof is in a sustained releaseformulation.
 19. The method of claim 1, wherein each of the naltrexoneor pharmaceutically acceptable salt thereof and bupropion orpharmaceutically acceptable salt thereof is in a sustained releaseformulation.
 20. A method for providing weight loss therapy to apatient, comprising: identifying a patient suffering from majordepressive disorder, wherein the patient is also overweight or obese;and reducing weight of the patient by administering to the patientnaltrexone or a pharmaceutically acceptable salt thereof and bupropionor a pharmaceutically acceptable salt thereof, wherein the amount of thenaltrexone or pharmaceutically acceptable salt thereof is about 32 mgper day; wherein the amount of the bupropion or pharmaceuticallyacceptable salt thereof is about 360 mg per day; and wherein each of thenaltrexone or pharmaceutically acceptable salt thereof and bupropion orpharmaceutically acceptable salt thereof is in a sustained releaseformulation.